ArticleEBioMedicine2019
Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 80 citations in OpenAlex.
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- Formation and Long-Term Culture of hiPSC-Derived Sensory Nerve Organoids Using Microfluidic Devices.Bioengineering (Basel, Switzerland) · 2024Article
- KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons.Biomedicines · 2024Article
- Mutation of the ALS-/FTD-Associated RNA-Binding Protein FUS Affects Axonal Development.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.Cells · 2024Review
- Dynamics of Chromatin Opening across Larval Development in the Urochordate AscidianInternational journal of molecular sciences · 2024Article
- Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury.Inflammation and regeneration · 2024Article
- Potential use of iPSCs for disease modeling, drug screening, and cell-based therapy for Alzheimer's disease.Cellular & molecular biology letters · 2023Review
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Authors and funding
31 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated.
methodTwo sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs possessing the single amino acid difference (p.H517D) in the fused in sarcoma (FUS) were constructed. By combining MN reporter lentivirus, MN specific phenotype was analyzed. Moreover, RNA profiling of isolated axons were conducted by applying the microfluidic devices that enable axon bundles to be produced for omics analysis. The relationship between the target gene, which was identified as a pathological candidate in ALS with RNA-sequencing, and the MN phenotype was confirmed by intervention with si-RNA or overexpression to hiPSCs-derived MNs and even in vivo. The commonality was further confirmed with other ALS-causative mutant hiPSCs-derived MNs and human pathology.
findingsWe identified aberrant increasing of axon branchings in FUS-mutant hiPSCs-derived MN axons compared with isogenic controls as a novel phenotype. We identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. The commonality of those phenotypes was further confirmed with other ALS causative mutation than FUS.
interpretationAnalyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching. FUND: Japan Agency for Medical Research and development; Japanese Ministry of Education, Culture, Sports, Science and Technology Clinical Research, Innovation and Education Center, Tohoku University Hospital; Japan Intractable Diseases (Nanbyo) Research Foundation; the Kanae Foundation for the Promotion of Medical Science; and "Inochi-no-Iro" ALS research grant.
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